This project investigates the neurobiological effects of the tricyclic antidepressant iprindole and the antimalarial agent chloroquine in rat brain. These amphiphilic cations, when administered daily for 5-6 weeks, elicit the widespread formation of intracellular lysosomal myeloid bodies in the nervous system and elsewhere. Results obtained to date indicate that iprindole and chloroquine produce a rapid (1 hour) activation of the lysosomal system in brain, as shown by a significant decrease in lysosomal enzyme latency in 0.3 M sucrose, and an increase in lysosomal membrane fragility on exposure to hypo-osmotic and chemical challenge in vitro. We shall investigate the ultrastructural, biochemical and metabolic effects of these agents in rat brain in relation to their intracellular concentration and subcellular distribution. Early ultrastructural changes affecting neurons and glia in cerebral and cerebellar cortex will be looked for in order to identify possible target organelles of drug action, and to assess the tempo of intracellular autophagy and myeloid body formation. Compositional changes in brain involving structural components, e.g., RNA, DNA, protein, lipids, and marker enzymes of organelles, e.g., mitochondria, lysosomes, endoplasmic reticulum, will be investigated. The effect of drugs on the turnover rates of protein in specific subcellular fractions, e.g., mitochondria, microsomes, lysosomes, will be investigated. The ability of myeloid bodies to engage in heterolysosome formation and in lysosomal digestion will be investigated cytochemically with horseradish peroxidase as a marker protein, and biochemically by the procedure of Mego & McQueen (1967). Particular attention will be directed to a biochemical characterization of the lipid an lipoprotein composition of drug-induced myeloid bodies and the rates of synthesis and degradation of key lipid and protein components.